Mutational analyses of the tumor suppressor gene PATCHED1 : Role in non-melanoma skin cancer and nevoid basal cell carcinoma

Skin cancer is the most common cancer in Western countries, with a rapidly increasing incidence. The majority of these tumors are non-melanoma skin cancer (NMSC). The most common NMSC is basal cell carcinoma (BCC) followed by squamous cell carcinoma (SCC). In the US more than 1.3 million NMSCs are diagnosed each year, while in Sweden approximately 43000 cases were diagnosed in 2006. BCCs are slow growing tumors that are locally invasive but rarely metastasize. In contrast, SCCs are rapidly growing, invasive and have a metastatic potential. Exposure to UV radiation is the most important risk factor for developing BCCs and SCCs, followed by fair skin. NMSC occurs mostly as sporadic cases, but is also associated with certain genetic diseases, including the Nevoid basal cell carcinoma syndrome (NBCCS). NBCCS is characterized by multiple BCCs, developmental defects and predisposition to other types of tumors. Additionally, Multiple-self healing squamous epithelioma (MSSE) is a genetic disease with tumors similar to SCCs, as its hallmark. Both the NBCCS and MSSE responsible gene(s) are mapped to 9q22.3. The following studies were performed in order to investigate the role of genetic components in the development of these diseases and in NMSCs. In Paper I, the NBCCS gene was further mapped to the 9q22.3 region and confirmed to be involved in familial and sporadic BCCs. Moreover, we obtained evidence that (a) the NBCCS gene is indeed a tumor suppressor gene (TSG) and (b) another TSG in the same chromosomal region is likely to have a role in the development of the squamous type of skin cancer. In Paper II, the NBCCS gene, PTCH1, was verified to be the gene underlying NBCCS in Swedish patients, as inactivating PTCH1 mutations in the blood from these patients were identified. We also obtained evidence that the PTCH1 gene is an important TSG involved in the development of both sporadic and familial BCCs. In Paper III, we investigated whether genetic alterations in the PTCH1 and XPA genes are critical for the development of the squamous type of skin cancer. However, no mutations but only a high degree of polymorphism of the PTCH1 gene could be detected. Therefore, both PTCH1 and XPA were excluded as of major importance for the development of this type of skin cancer. It is likely that other gene(s), distal to PTCH1, are involved in SCCs development. The PTCH1 gene is mutated in different cancer types, but mainly in BCCs and other tumors associated with NBCCS. To better understand the role of PTCH1 in human disease, a locus-specific database, the PTCH Mutation Database, was set up in order to collect all relevant mutations. In Paper IV, the distribution pattern of PTCH1 mutations and single nucleotide polymorphisms that were compiled from the database were investigated. Unique distribution and mutation-type patterns that characterize the NBCCS disease, sporadic BCCs, BCCs from Xeroderma pigmentosum patients and sporadic medulloblastomas were identified. Additionally, domains and regions in the PTCH1 protein that are critical in the development of sporadic tumors and NBCCS were revealed. Conclusion: PTCH1 mutations result in deregulated Hedgehog signaling and are of major importance in the pathogenesis of NBCCS and BCCs but not SCCs